Female sexual dysfunction treatment

ABSTRACT

Sexual dysfunction in human females can be ameliorated, without substantial undesirable side effects, by apomorphine. Administration of apomorphine increases nerve stimulated clitoral intracavernosal blood flow and vaginal wall blood flow for enhanced clitoral erection and vaginal engorgement in a female. A plasma concentration of apomorphine of no more than about 5.5 nanograms per milliliter is preferably maintained.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of U.S. Ser. No. 09/016,252,filed on Jan. 30, 1998, now U.S. Pat. No. 5,945,117.

FIELD OF THE INVENTION

This invention relates to methods for ameliorating female sexualdysfunction.

BACKGROUND OF THE INVENTION

Apomorphine is a dopamine receptor agonist that has been widely utilizedas an emetic agent, sedative, antiparkinsonian agent as well as abehavior altering agent. Recent research and clinical studies havedemonstrated that in males apomorphine has an erectogenic effectmanifested by penile erection.

The effect of apomorphine on female sexual functionality has not beenpreviously investigated. Females also can have sexual dysfunction,however, that increases with age. Female sexual dysfunction usually isassociated with the presence of vascular risk factors, genital smoothmuscle atrophy, and onset of menopause. Some of the vascular andmuscular mechanisms that contribute to penile erection in the male arebelieved to be similar vasculogenic factors in female genital response.It is known that in women sexual arousal is accompanied by arterialinflow which engorges the vagina and increases vaginal lubrication, andthat the muscles in the perineum assist in achieving clitoral erection.

In the female patient, sexual dysfunction can arise from organic andpsychogenic causes, or from a combination of the foregoing. Femalesexual dysfunction includes a failure to attain or maintain vaginallubrication-swelling responses of sexual excitement until completion ofthe sexual activity. Organic female sexual dysfunction is known to berelated in part to vasculogenic impairment resulting in inadequate bloodflow, vaginal engorgement insufficiency and clitoral erectioninsufficiency.

Female sexual dysfunction has not been studied as extensively as malesexual dysfunction. This has partly been due to historical belief thatfemale sexual dysfunction was orgasmic-related (delayed or non-orgasmic)or libido, and hence lacked an appropriate animal model.

The use of New Zealand White male rabbits as animal models for impotencehas been well established. More recently, studies have reported that NewZealand White female rabbits are also suitable animal model for studyingthe vascular pathology in female sexual dysfunction. Such studies haveshown that vaginal vascular engorgement and clitoral erection depend onblood inflow. See, for example, Park et al, “Vasculogenic female sexualdysfunction: the hemodynamic basis for vaginal engorgement insufficiencyand clitoral erectile insufficiency,” International Journal of ImpotenceResearch, 9, (1), 27-37 (March 1997).

For psychogenic sexual dysfunction management, psychological sex therapycan also be employed to help the patient.

Apomorphine previously was shown to have very poor oral bioavailability.See, for example, Baldessarini et al., in Gessa et al., (eds.),Apomorphine and Other Dopaminomimetics, Basic Pharmacology, 1, 219-228,Raven Press, N.Y. (1981).

More recently, studies with males show that oral administration ofapomorphine can be used to induce an erection in a psychogenic malepatient, as long as the apomorphine dose required to achieve asignificant erectile response is not accompanied by nausea and vomitingor other serious undesirable side effects such as arterial hypotension,flushing and diaphoresis. See U.S. Pat. No. 5,624,677 to El-Rashidy etal. and Heaton et al., Urology, 45, 200-206 (1995). The specificmechanisms by which apomorphine acts to produce an erectile response ina human patient are not yet completely understood but are believed to becentrally acting through dopamine receptor stimulation in the medialpreoptic area of the brain.

It has now been found that certain controlled delivery systems forapomorphine can provide a practical therapeutic use in amelioratingsexual dysfunction in human females while reducing the likelihood ofundesirable side effects.

SUMMARY OF THE INVENTION

Administration of apomorphine to a human female increases nervestimulated clitoral intracavernosal blood flow and vaginal wall bloodflow, each of which is associated respectively with enhanced clitoralerection and vaginal engorgement in a female.

A sublingual apomorphine dosage form, usually containing about 2 toabout 12 milligrams, preferably about 2 to about 8 milligrams, ofapomorphine, is preferred for producing sexual readiness in humanfemales without inducing substantial nausea or other undesirable sideeffects. Other dosage forms can be utilized as well.

Administration of apomorphine in an amount sufficient to produce vaginalengorgement is effected preferably about 15 to about 20 minutes prior tosexual activity. The plasma concentration of apomorphine is maintainedat no more than about 5.5 nanograms per milliliter, preferably about 0.3to about 4 nanograms per milliliter, and more preferably about 1 toabout 2 nanograms per milliliter, so as to maintain a circulating serumlevel and mid-brain tissue level of apomorphine during the period ofsexual activity sufficient to maintain vaginal engorgement, itsassociated lubrication and clitoral erection during coitus, but lessthan the amount that induces substantial nausea.

While sublingual administration of apomorphine is preferred for presentpurposes, other routes of administration are also suitable. Illustrativeof such alternate routes of administration are buccal patch, transdermalpatch, cream, ointment, intranasal spray, tablets, capsules and thelike.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings,

FIG. 1 is a bar graph depicting the effect of apomorphine on femalerabbit clitoral blood flow in milliliters per minute per 100 gramstissue before and after nerve stimulation for placebo and intravenousapomorphine amounts of 0.05, 0.1, 0.2, 0.3 and 0.4 milligrams perkilogram body weight;

FIG. 2 is a bar graph depicting the effect of apomorphine on femalerabbit vaginal wall blood flow in milliliters per minute per 100 gramstissue before and after nerve stimulation for placebo and intravenousapomorphine amounts of 0.05, 0.1, 0.2, 0.3 and 0.4 milligrams perkilogram body weight; and

FIG. 3 is a graph depicting the effect of intravenous apomorphine onfemale rabbit systemic (diastolic and systolic) arterial pressure.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Apomorphine can be represented by the following formula

and exists in a free base form or as an acid addition salt. For thepurposes of the present invention apomorphine hydrochloride ispreferred; however, other pharmacologically acceptable moieties thereofcan be utilized as well. The term “apomorphine” as used herein includesthe free base form of this compound as well as the pharmacologicallyacceptable acid addition salts thereof. In addition to the hydrochloridesalt, other acceptable acid addition salts are the hydrobromide, thehydroiodide, the bisulfate, the phosphate, the acid phosphate, thelactate, the citrate, the tartrate, the salicylate, the succinate, themaleate, the gluconate, and the like.

Apomorphine is a dopamine receptor agonist that has been recognized alsoas an emetic when administered subcutaneously in about a 5-milligramdose. For the purposes of the present invention, apomorphine isadministered in an amount sufficient to excite cells in the mid-brainregion of the patient but with minimal side effects. This cellexcitation is believed to be part of a cascade of stimulation that islikely to include neurotransmission with serotonin and oxytocin.

It is known from studies with males that the dopamine receptors in themid-brain region of a male patient can be stimulated to a degreesufficient to cause an erection by the sublingual administration ofapomorphine so as to maintain a plasma concentration of apomorphine ofno more than about 5.5 nanograms per milliliter (5.5 ng/ml).

The pharmacokinetics of apomorphine are the same for both females andmales, based on apomorphine hydrochloride studies with humans(Parkinson's disease) and animals reported in the literature. Thus, theonset and duration of effect from a given dose of apomorphine in mencompared to animals applies to human females as well.

It was found that an intravenous dosage of apomorphine of about 100micrograms per kilogram (μg/kg) of body weight was optimum for producinga vasculogenic effect on nerve stimulated vaginal and clitoral bloodflow in female rabbit studies. For human females, this dosage correlatesto an optimum dosage of about {fraction (1/10)} or 10 μg/kg of bodyweight. In sublingual tablet forms, the bioavailability of apomorphineis about 13% compared to subcutaneously administered apomorphinehydrochloride. Assuming an average female body weight of about 70kilograms, a significant sexual readiness dose of apomorphine is about76 μg/kg or about a 5.3 milligram (mg) per tablet. A dosage range ofabout 2 mg to about 12 mg, therefore, produces sexual readiness (i.e.,clitoral erectogenesis and vaginal engorgement on sexual stimulation) inwomen.

Sublingual administration preferably takes place over a time period inthe range of about 2 to about 10 minutes, or longer, more preferablyabout 15 to about 20 minutes, prior to sexual activity. The amount ofapomorphine administered sublingually to a human female over this timeperiod preferably is in the range of about 25 μg/kg of body weight toabout 80 μg/kg of body weight.

Illustrative preferred sublingual dosage forms are set forth in Table I,below.

TABLE I 150 Milligram Apomorphine Hydrochloride Sublingual Tablets 3-mgTablet Apomorphine Hydrochloride 2.00 wt-% Mannitol 66.67 wt-% AscorbicAcid 3.33 wt-% Citric Acid 2.00 wt-% Avicel PH102¹ 15.00 wt-% MethocelE4M² 10.00 wt-% Aspartame 0.67 wt-% Magnesium Stearate 0.33 wt-% 4-mgTablet Apomorphine Hydrochloride 2.66 wt-% Mannitol 66.00 wt-% AscorbicAcid 3.33 wt-% Citric Acid 2.00 wt-% Avicel PH102¹ 15.00 wt-% MethocelE4M² 10.00 wt-% Aspartame 0.67 wt-% Magnesium Stearate 0.33 wt-% 5-mgTablet Apomorphine Hydrochloride 3.33 wt-% Mannitol 65.34 wt-% AscorbicAcid 3.33 wt-% Citric Acid 2.00 wt-% Avicel PH102¹ 15.00 wt-% MethocelE4M² 10.00 wt-% Aspartame 0.67 wt-% Magnesium Stearate 0.33 wt-%¹microcrystalline cellulose ²hydroxypropylmethyl cellulose

If desired, and in order to facilitate absorption and thusbioavailability, the presently contemplated dosage forms can alsocontain, in addition to tabletting excipients, a β-cyclodextrin or aβ-cyclodextrin derivative such as hydroxypropyl-β-cyclodextrin (HPBCD).Illustrative dosage forms containing HPBCD are shown in Tables II andIII, below.

TABLE II Apomorphine Hydrochloride Sublingual Tablets WithHydroxypropyl-β-Cyclodextrin mg/Tab Apomorphine Hydrochloride 4.0 HPBCD5.0 Ascorbic Acid 10.0 PEG8000 39.5 Mannitol 39.5 Aspartame 2.0 TOTAL100.0

TABLE III Apomorphine Hydrochloride Sublingual Tablets Withβ-Cyclodextrin mg/Tab Apomorphine Hydrochloride 5.0 β-Cyclodextrin 20.0Ascorbic Acid 5.0 Mannitol 68.9 Magnesium Stearate 1.0 D&C Yellow 10Aluminum Lake 0.1 TOTAL 100.0

Additional sublingual apomorphine dosage forms are illustrated in TableIV, below. The amounts of apomorphine are expressed as apomorphinehydrochloride hemihydrate.

TABLE IV Sublingual Apomorphine Tablets Amount per Tablet (mg)Apomorphine-HCl, USP 2, 4, 6 or 8 Mannitol, USP QS Avicel PH 102 NF¹22.7 HPMC 2910, Type E4M Premium, USP/NF² 5.0 Citric Acid, Anhydrous,USP 2.0 Ascorbic Acid, USP/NF 3.0 Magnesium Stearate, NF 1.2 Color Agent1.2 Sweetener 1.0 Total Tablet Weight, mg 60.0 Apomorphine-HCl, USP 2,3, 4, 5, or 6 Mannitol, USP QS Avicel PH 102 NF¹ 20.0 HPMC 2910, TypeE4M Premium, USP/NF² 10.0 Citric Acid, Anhydrous, USP 3.5 Ascorbic Acid,USP/NF 0.2 Edetate Disodium Dihydrate, USP/NF 0.1 Colloidal SiliconDioxide, NF 0.1 Magnesium Stearate, NF 1.5 Color Agent 2.0 Flavoring 2.0Sweetener 2.0 Total Tablet Weight, mg 100.0 ¹microcrystalline cellulose²hydroxypropylmethyl cellulose

The onset of nausea can be obviated or delayed by delivering apomorphineat a controlled dissolution rate so as to provide circulating serumlevels and mid-brain tissue levels of apomorphine sufficient for vaginaland clitoral engorgement without inducing nausea. When apomorphine isadministered at or near the relatively higher amounts of theaforementioned dosage range, the likelihood of nausea onset can bereduced by concurrent administration of a ganglionic agent (inhibitor ofganglionic response) such as nicotine or lobeline sulfate. For thispurpose, the weight ratio of apomorphine to ganglionic agent is in therange of about 10 to about 1.

Other antiemetic agents that can be used in conjunction with apomorphineare antidopaminergic agents such as metoclopramide, and thephenothiazines, e.g., chlorpromazine, prochlorperazine, pipamazine,thiethylperazine, oxypendyl hydrochloride, and the like. Also suitableare the serotonin (5-hydroxytryptamine or 5-HT) antagonists such asdomperidone, odansetron (commercially available as the hydrochloridesalt under the designation Zofran®), and the like, the histamineantagonists such as buclizine hydrochloride, cyclizine hydrochloride,dimenhydrinate (Dramamine), and the like, the parasympatheticdepressants such as scopolamine, and the like, as well as otheranti-emetics such as metopimazine, trimethobenzamide, benzquinaminehydrochloride, diphenidol hydrochloride, and the like.

Nicotine-containing dosage forms and domperidone-containing dosage formsare illustrated in Table V, below.

TABLE V Apomorphine Hydrochloride Sublingual Tablets Containing anAnti-Emetic Agent mg/Tab Apomorphine Hydrochloride 5.0 Ascorbic Acid 5.0Mannitol 67.9 Magnesium Stearate 1.0 Nicotine 1.0 β-Cyclodextrin 20.0D&C Yellow 10 Aluminum Lake 0.1 TOTAL 100.0 Apomorphine Hydrochloride5.0 Ascorbic Acid 5.0 Mannitol 58.9 Magnesium Stearate 1.0 Domperidone10.0 β-Cyclodextrin 20.0 D&C Yellow 10 Aluminum Lake 0.1 TOTAL 100.0

The preferred sublingual dosage forms dissolve within a time period ofat least about 2 minutes but preferably less than about 10 minutes. Thedissolution time can be longer, however, if desired as long as thenecessary plasma concentration of apomorphine can be maintained. Morepreferably, the dissolution time in water for the presently contemplateddosage forms is about 3 minutes to about 5 minutes.

Controlled slow release sublingual or buccal dosage forms of apomorphinesuitable for practicing the present invention are described in U.S. Pat.No. 5,624,677 to El-Rashidy et al. and in U.S. Pat. No. 5,888,534 toEl-Rashidy et al.

Suitable transdermal patches and water-soluble gels for the topicaladministration of apomorphine in practicing the present invention aredescribed in U.S. Pat. No. 5,562,917 to Durif and El-Rashidy.

Gel-forming polymer useful for compounding the apomorphine compositionsmay be any suitable polymer which is hydrophilic and water-dispersible,has free carboxylic groups, and forms a gel of substantially uniformconsistency. Illustrative such polymers are the polysaccharides such asalgin, xanthan, guar and the like, and synthetic hydrophilic polymerssuch as the alkyl celluloses, hydroxyalkyl celluloses, polyvinylsufonates, polyacrylates, polyacrylamides and the like. Preferredpolymers for use in the compositions of the invention are hydroxypropylmethylcellulose and water dispersible polycarboxylated vinyl polymers.Polyacrylic acid polymers are particularly preferred for the presentpurposes. The molecular weight of the polymer is desirably in the rangeof about 1,250,000 to about 4,000,000. Suitable polyacrylic acidpolymers include, but are not limited to, polyacrylic acid polymerslightly cross-linked with a polyalkenyl polyether such as thosecommercially available from B.F. Goodrich, Cincinnati, Ohio, under thetrademarks Carbopol 934, 940, and 941. Carbopol 934® is a particularlypreferred polymer for this purpose.

The polymer is present in an amount sufficient to cause gelling of thecomposition and impart the desired viscous consistency to the topicalformulation. The apomorphine compositions advantageously comprise about0.1 to about 7% by weight of the polymer, preferably about 0.5% to about1.5%, and most preferably about 1% by weight of the polymer, based onthe total weight of the composition.

Aqueous solutions of these polymers form gels when neutralized with abase. Water-soluble bases which may be used to promote gelling ofpolymers such as Carbopols™ include inorganic bases such as an aqueoussolution of ammonium hydroxide, NaOH, and organic amines, e.g.,alkylamines such as methylamine and ethylamine, dialkylaminestrialkylamines, alkanolamines, dialkanolamines, and the like.

One preferred dosage form for practicing the present invention utilizesan aqueous gel or cream composition which contains apomorphine and askin permeation enhancer therefor. Another dosage form utilizes apressure-sensitive medical grade silicone adhesive matrix which containsapomorphine and a permeation enhancer therefor. Other suitable dosageforms are rectal and vaginal suppositories, buccal patches, tablets,capsules, and the like.

A contemplated skin permeation enhancer is an aromatic or aliphaticcarbocyclic compound containing pendant hydroxyl groups, such asbutylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA) or ahydroxypropyl-beta-cyclodextrin (HPBCD), and the like, which can bepresent in amount up to about 30 percent by weight of the gel or theadhesive matrix.

Apomorphine is present in the dosage form for purposes of the presentinvention in an amount in the range of about 0.1 to about 3 percent byweight of the gel or the adhesive matrix.

Illustrative suitable intranasal spray composition that can be used forpracticing the present invention is as follows:

Apomorphine-HCl, USP 4 mg/ml Na₂S₂O₆ 0.05 wt.-% Methyl paraben 0.1 wt.-%Propyl paraben 0.02 wt.-% NaCl 0.8 wt.-% purified water, USP q.s.

The following examples further illustrate the vasculogenic effect ofapomorphine on vaginal and clitoral blood flow in females, employing anappropriate female animal model.

Methods

New Zealand White female rabbits (n=6, about 3.5-4 kg) were anesthetizedwith intravenous administration of pentobarbital. A 20 gaugeangiocatheter was placed into the right carotid artery for measurementof systemic arterial pressure. A midline abdominal incision was made andthe pelvic nerve branch to the vagina and clitoris was dissected. Nervestimulation was performed with a Harvard subminiature electrode placedaround the pelvic nerve branch to the vagina and clitoris and connectedto a Grass SD-9 stimulator. Clitoral intracavernosal and vaginal wallblood flow were measured with a laser Doppler flow probe placed directlyinto the clitoral cavernosal tissue or into the vaginal wall andconnected to a laser Doppler flowmeter.

Basal arterial blood pressure and clitoral and vaginal blood flow wereeach recorded before and then after stimulation of the pelvic nervebranch to the clitoris and vagina. After this, apomorphine wasadministered through the ear vein in a dose response manner (0.05 mg/kg,0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg and 0.4 mg/kg). The effect ofapomorphine administration on arterial blood pressure and clitoral andvaginal blood flow were each recorded before and then after nervestimulation.

Results

1. Effect of apomorphine on clitoral intracavernosal blood flow.

Stimulation of the pelvic nerve branch to the vagina and clitoris causeda significant increase in clitoral intracavernosal blood flow.Intravenous administration of apomorphine did not affect baselineclitoral intracavernosal blood flow. Intravenous administration ofapomorphine at concentrations of 0.05 mg/kg to 0.2 mg/kg caused aconcentration dependent increase in nerve stimulation-induced peakclitoral intracavernosal blood flow, as depicted graphically in FIG. 1.In particular, apomorphine at 0.1 mg/kg, 0.2 mg/kg and 0.3 mg/kg causeda statistically significant increase in nerve stimulation-induced peakclitoral intracavernosal blood flow compared to that observed beforeapomorphine administration (FIG. 1).

2. Effect of apomorphine on vaginal wall blood flow.

Intravenous administration of apomorphine did not affect basal vaginalwall blood flow. Apomorphine at concentrations of 0.05 and 0.2 mg/kgcaused a concentration dependent increase in nerve stimulation-inducedpeak vaginal wall blood flow, as graphically depicted in FIG. 2.Intravenous administration of 0.1 and 0.2 mg/kg apomorphine caused astatistically significant increase in nerve stimulation-induced peakvaginal wall blood flow compared to that observed before apomorphineadministration (FIG. 2).

Apomorphine at concentration of 0.4 mg/kg produced an adverse effect onnerve stimulation-induced increase in vaginal wall blood flow.

3. Effect of apomorphine on systemic arterial pressure.

The effect of increasing doses of apomorphine on diastolic arterialpressure is shown in FIG. 3. Intravenous administration of apomorphinecaused a concentration dependent moderate decrease in diastolic arterialpressure while having minimal effect on systolic arterial pressure.

Conclusion

Intravenous administration of apomorphine at a concentration of 0.1mg/kg, 0.2 mg/kg and 0.3 mg/kg caused a significant increase in nervestimulation-induced peak clitoral intracavernosal blood flow.Intravenous administration of apomorphine at a concentration of 0.1mg/kg and 0.2 mg/kg caused a significant increase in vaginal wall bloodflow. The main side effect of intravenous administration of apomorphinenoted was a moderate decrease in diastolic blood pressure. A dose ofabout 0.1 mg/kg was judged optimal.

Studies with this female rabbit model showed that the hemodynamicmechanisms of clitoral erection and vaginal engorgement depend on therelaxation of clitoral cavernosal and vaginal wall smooth muscle. It isalso known that in the human female, vasocongestion of the vaginaentails lubrication of the vagina and swelling of the external genitaliaduring sexual excitation. Thus, the enhancement of clitoral blood flowby apomorphine in the female rabbit was judged indicative of improvingclitoral erection, and the enhancement of vaginal blood flow byapomorphine was judged indicative of increasing vaginal lubrication andaugmenting vaginal engorgement in human females.

It is known that dosage ranges with apomorphine hydrochloride arespecies dependent. In humans, the effective dosage compared to animalsis about {fraction (1/10)}. Thus, an optimum dose of about 0.1 mg/kggiven intravenously, based on the female rabbit study would correlate toan effective dose of about 0.01 mg/kg in a human female. Sincesublingual administration of apomorphine is known to provide about 13%bioavailability compared to subcutaneous administered apomorphine, adosage of about 76 micrograms/kg or about 5.3 mg tablet for a 70 kgweight woman produces a significant sexual readiness (clitoralerectogenesis and vaginal engorgement on sexual stimulation). Thus, adosage range of about 2 to about 12 mg, preferably about 2 to about 8mg., more preferably about 4 to about 6 mg. is sufficient for producingsexual readiness in women without inducing substantial nausea.

The foregoing discussion and the reported studies are intended asillustrative of the present invention and are not to be taken aslimiting. Still other variants within the spirit and scope of thisinvention are possible and will readily present themselves to thoseskilled in the art.

We claim:
 1. A method of ameliorating sexual dysfunction in a humanfemale which comprises administering to said human female apomorphine inan amount sufficient to increase intraclitoral blood flow and vaginalwall blood flow on stimulation of said female but less than the amountthat induces substantial nausea.
 2. The method in accordance with claim1 wherein the apomorphine is administered in a sublingual dosage formcontaining about 2 milligrams to about 12 milligrams of apomorphine. 3.The method in accordance with claim 1 wherein the amount of apomorphineadministered is in the range of about 25 to about 80 micrograms perkilogram of body weight.
 4. The method in accordance with claim 1wherein the apomorphine is administered as the hydrochloride salt. 5.The method in accordance with claim 1 wherein the apomorphine isadministered together with a β-cyclodextrin.
 6. The method in accordancewith claim 1 wherein the β-cyclodextrin is hydroxypropyl-β-cyclodextrin.7. A method of stimulating dopamine receptors in the mid-brain region ofa human female to cause clitoral erectogenesis and vaginal engorgementwhich comprises administering to the human female apomorphine about 25to about 80 micrograms of apomorphine per kilogram of body weight and ata rate so as to maintain a plasma concentration of apomorphine of nomore than about 5.5 nanograms per milliliter during sexual activity. 8.The method in accordance with claim 7 wherein the plasma concentrationof apomorphine is maintained in the range of about 0.3 to about 4nanograms per milliliter during sexual activity.
 9. The method inaccordance with claim 7 wherein the plasma concentration of apomorphineis maintained in the range of about 1 to about 2 nanograms permilliliter during sexual activity.
 10. A method of ameliorating sexualdysfunction in a human female which comprises administering to saidhuman female apomorphine in an amount sufficient to stimulation induceclitoral erectogenesis and vaginal engorgement and to maintain a plasmaconcentration of apomorphine at a level of no more than about 5.5nanograms per milliliter.
 11. The method in accordance with claim 10wherein the plasma concentration of apomorphine is maintained at a levelof about 0.3 to about 4 nanograms per milliliter.
 12. The method inaccordance with claim 10 wherein the plasma concentration of apomorphineis maintained at a level of about 1 to about 2 nanograms per milliliter.13. The method in accordance with claim 10 wherein the amount ofapomorphine administered is in the range of about 2 milligrams to about12 milligrams.
 14. The method in accordance with claim 10 wherein theamount of apomorphine administered is in the range of about 25 to about80 micrograms per kilogram of body weight.
 15. The method in accordancewith claim 10 wherein apomorphine is administered as the hydrochloridesalt.
 16. The method in accordance with claim 1 wherein theadministration is effected by a transdermal patch.
 17. The method inaccordance with claim 1 wherein the administration is effected by theapplication of a cream to the clitoral region of the patient.
 18. Themethod in accordance with claim 1 wherein the administration is effectedby a buccal patch.